The principal goal of this research program (GM-29028) has been and will continue to be, the development of efficient, enantiospecific synthetic strategies for the construction of architecturally novel macrolides possessing significant pharmacological properties. During the first grant period (01-03), we achieved the first total synthesis of milbemycin beta 3, the simplest member of the avermectin-milbemycin family of anthelmintic macrolide antibiotics. Currently we have underway two viable strategies for the southern hemisphere of the milbemycin-avermectin targets. Prospects for the completion of milbemyucin alpha 1 are excellent. As a new target for the 08-11 years, we have selected the immunosuppressant FK506 (12), a novel 23-membered macrolide recently isolated by the Fujisawa Pharmaceutical Co., Ltd. from Streptomyces tsukubaensis no. 9993. Over the past ten years, the introduction of powerful immunosuppressants has led to tremendous advances in the area of human organ transplantation. Post-operative graft rejection however continues to be the foremost problem currently faced by transplant surgeons. The discovery and development of new immunosuppressant drugs is therefore of utmost importance to transplant surgery. FK506 appears to be an exceptionally promising candidate: in vivo, it inhibits T-lymphocytes, MLR, generation of killer T cells and appearance of IL-2 receptors, and thereby hypersensitivity reactions, at 30-100 times lower concentration than cyclosporin A, the most effective immunosuppressant available to date. FK506 is therefore an important target for total synthesis, not only for its intrinsic synthetic challenge, but also due to its extrinsic worth to the field of medicine.